CNS Drugs

, Volume 15, Issue 11, pp 871–904 | Cite as

Olanzapine

A Review of its Use in the Treatment of Bipolar I Disorder
Adis Drug Evaluation

Summary

Abstract

Olanzapine, a thienobenzodiazepine derivative, is a psychotropic agent that has shown efficacy in the treatment of patients with bipolar I disorder. Olanzapine has a multireceptorial binding profile including a greater affinity for serotonin 5-HT2A than for dopamine D2 receptors.

Olanzapine 5 to 20 mg/day demonstrated significantly greater antimanic efficacy than placebo in two double-blind, randomised 3- or 4-week trials of patients with bipolar I disorder of either manic or mixed episodes, with or without psychotic features. Additionally, in one of these trials, improvements in cognitive function and hostility were superior with olanzapine. In cohorts of severely depressed and rapid cycling patients, improvements in manic and depressive symptoms and in manic symptoms only, were superior with olanzapine compared with placebo. Significant improvements from baseline in symptoms of mania, depression, cognitive functioning and hostility were seen with olanzapine in a 49-week extension phase study.

In double-blind trials, olanzapine 10 mg/day appeared to have similar antimanic efficacy to oral lithium 400mg twice daily in the treatment of patients with pure mania (4-week small study). In patients with acute manic or mixed episodes olanzapine 5 to 20 mg/day appeared to be more effective than oral valproate semisodium (divalproex sodium) 500 to 2500 mg/day (3-week study) and at least as effective as oral haloperidol 3 to 15 mg/day (12-week study).

Preliminary results from a large 6-week placebo-controlled study suggest that olanzapine 5 to 20 mg/day in combination with mood stabilisers (lithium or valproate semisodium) provides effective augmentation of antimanic treatment of patients with bipolar I disorder, with benefits seen in the first week.

Adverse events reported significantly more often with olanzapine than with placebo were somnolence, dry mouth, dizziness and bodyweight gain, and in comparison with valproate semisodium were somnolence, dry mouth, increased appetite and bodyweight gain. Olanzapine was generally well tolerated with no clinically relevant abnormalities in laboratory tests, vital signs or electrocardiogram results.

Conclusion: Olanzapine demonstrated superior efficacy compared with placebo in the short-term treatment of patients with bipolar I disorder with manic or mixed episodes, with or without psychotic features, and was generally well tolerated. According to preliminary data the antimanic efficacy of olanzapine appears similar to that of haloperidol and better than that of valproate semisodium in patients with bipolar I disorder experiencing a manic or mixed episode; among nonpsychotic patients with manic or mixed episodes olanzapine appears to be superior to haloperidol. Available data support the choice of olanzapine as an option in the short-term management of mania in patients with bipolar I disorder with manic or mixed episodes, with or without psychotic features.

Pharmacodynamic Properties

Olanzapine, a thienobenzodiazepine derivative, is a psychotropic agent which has binding affinity for a broad range of neurotransmitter receptors. In vitro olanzapine is a potent antagonist at serotonin 5-HT2A-C, α1-adrenergic and histamine H1 receptors, a relatively modest antagonist at dopamine D1 and all five subtypes of the muscarinic receptor, and is devoid of agonist activity at any of these receptors. The mixed receptor activity of olanzapine is similar to that of clozapine, as is its greater affinity for 5-HT2A than for D2 receptors.

Olanzapine exhibits a preclinical behavioural profile that is indicative of antipsychotic activity. Inhibition of a number of dopamine and serotonin agonist-induced animal behaviours was demonstrated in vivo, confirming in vitro evidence of its receptor affinity profile. Olanzapine blocked conditioned avoidance at lower doses than those inducing catalepsy and reduced behaviours predictive of positive and negative symptoms. Olanzapine increased noradrenaline and dopamine release in cortical areas which may contribute to its effects against negative symptoms.

In electrophysiological studies, olanzapine demonstrated mesolimbic (A10) over nigrostriatal (A9) selectivity, which may be predictive of a low potential for the induction of extrapyramidal symptoms (EPS).

Olanzapine is not associated with cognitive dysfunction but may improve neurocognitive deficits, as seen in patients with schizophrenia. Spatial memory capacity (a cognitive indicator) was not impaired after a morning dose of olanzapine 5mg alone or in combination with imipramine 75mg in healthy volunteers and short-term effects on alertness and motor effects showed rapid adaptation to treatment. In healthy volunteers olanzapine showed sleep-promoting effects.

Olanzapine was not associated with clinically significant prolonged rate-corrected QT (QTc) interval or hyperprolactinaemia in clinical trials of patients with acute psychosis or bipolar I disorder. There are a number of case reports of treatment-emergent diabetes mellitus and a few of diabetic ketoacidosis or hyperosmolar states.

Bodyweight gain with olanzapine in short-term clinical trials was significantly greater than that seen with placebo or valproate semisodium (divalproex sodium).

Pharmacokinetic Properties

Olanzapine is well absorbed after oral administration in healthy volunteers and the absolute oral bioavailability (60 to 80%) is unaffected by food. Mean peak plasma concentrations (Cmax) of 11 μg/L after a single oral dose of 12.5mg are achieved in approximately 5 hours (tmax). Steady-state plasma concentrations are seen after about 7 days’ treatment with olanzapine. The volume of distribution is 22 L/kg and the drug is highly (93%) protein bound in plasma. In vitro about 5 to 14% of olanzapine crosses the placenta.

Olanzapine is extensively metabolised by glucuronidation (facilitated by uridine diphosphate glucuronyltransferase) and oxidation [by the cytochrome P450 (CYP) 1A2 and 2D6 isoenzymes and the flavin-containing mono-oxygenase-3 system] to the major metabolites 10-N-glucuronide and 4′-N-desmethyl olanzapine and about 8 other inactive metabolites. The elimination half-life (t1/2β) of olanzapine is about 30 hours for healthy volunteers and is prolonged in female and elderly individuals. The clearance (CL) of olanzapine ranges from 12 to 47 L/h in healthy volunteers but is decreased in females and elderly individuals. The pharmacokinetics of olanzapine were not significantly altered in patients with renal or hepatic dysfunction.

Some inhibitors of CYP1A2 (fluvoxamine, ciprofloxacin) and CYP2D6 (fluoxetine) increase the plasma concentration of olanzapine by 40 to 100%, and some CYP1A2 inducers, such as cigarette smoking and carbamazepine, increase the apparent CL of olanzapine by about 23 to 46%, respectively.

Therapeutic Efficacy

Olanzapine (5, 10, 15 or 20mg once daily for 3 or 4 weeks) significantly improved manic symptoms in two double-blind trials of patients (n = 254) aged 18 to 70 years with bipolar I disorder of either manic or mixed episodes with or without psychotic features. Improvements from baseline Young-Mania Rating Scale (Y-MRS) scores to endpoint, according to last observation-carried-forward analysis, were significantly greater with olanzapine than placebo (36 and 51% vs 18 and 28%, p < 0.05). In the 4-week trial, superiority compared with placebo was seen as early as week 1; the starting dosage in this trial was 15 mg/day compared with 10 mg/day in the 3-week trial. No significant difference in improvements was seen between patients experiencing manic or mixed episodes or those with or without psychotic features. Additionally, clinical response (defined as ≥50% improvement from baseline to endpoint Y-MRS total score) was seen in more olanzapine than placebo recipients in both trials (49 and 65% vs 24 and 43%, p < 0.05). Secondary efficacy measures showed significantly greater improvements in cognitive functioning and hostility with olanzapine than with placebo in the 3-week trial.

Post hoc analysis of a cohort of patients (n = 68) from these trials with depression of at least moderate severity showed that improvements from baseline to endpoint in Y-MRS (40 vs 15% ) and Hamilton Depression Rating Scale (HAM-D) [44 vs 27%] scores (rating manic and depressive symptoms, respectively) were significantly greater with olanzapine 5 to 20 mg/day than placebo. Similarly, in a cohort of patients with rapid cycling bipolar I disorder (n = 44), improvements in mania were superior with olanzapine compared with placebo (−14 vs −4, τ < 0.05). Significantly more olanzapine than placebo recipients showed ≥30% improvement from baseline Y-MRS scores (84 vs 36%, p = 0.002).

During nonblind treatment with olanzapine (n = 113), in the extension phase (49 weeks) of the 3-week acute phase study, superior (p < 0.001) improvements from baseline were observed for symptoms of mania (71%), depression (47%), cognitive functioning (36%) and hostility (42%).

Olanzapine 10 mg/day was as effective as lithium 400mg twice daily in a 4-week double-blind trial of patients (n = 30) with bipolar I disorder experiencing a pure manic episode. No significant between-treatment difference was seen in improvements from baseline scores on the Brief Psychiatric Rating Scale or the Mania Rating Scale, although superior improvements were seen with olanzapine on the Clinical Global Impressions severity score (51 vs 38%, p < 0.05). Important limitations of this trial include the low mean serum lithium concentration (0.74 mmol/L), the doses of both lithium and olanzapine were low compared with other relevant studies and the study was small.

Compared with valproate semisodium 500 to 2500 mg/day (in divided doses) olanzapine 5 to 20 mg/day improved symptoms of mania (according to Y-MRS total score) to a significantly greater extent (49 vs 37%, p < 0.05) in a 3-week double-blind trial of patients (n = 251) with either manic or mixed episodes. In these preliminary results (poster presentation) there was no significant between-treatment difference in the percentage of responders; however, improvements of depressive symptoms were greater with olanzapine, and significantly more olanzapine than valproate semisodium recipients achieved remission (defined as having a Y-MRS score ≤12) [47 vs 34%, p < 0.05].

Chart reviews showed olanzapine 5 to 30 mg/day to be beneficial as adjunctive therapy in patients with treatment-resistant bipolar disorder. Additionally, a few case reports and one noncomparative study have suggested some efficacy in the treatment of children with bipolar disorder. According to retrospective chart reviews and case reports olanzapine, when combined with mood stabilisers (mostly lithium and valproate semisodium), provides effective augmentation of mood stabilising and antimanic treatment of patients with bipolar I disorder and preliminary results from a large (n = 344) 6-week, double-blind study support these findings. Addition of olanzapine 5 to 20 mg/day to an existing treatment regimen of valproate semisodium (50 to 125 μg/ml serum concentration) or lithium (0.6 to 1.2 mmol/L serum concentration) improved Y-MRS total scores to a significantly greater extent than the mood stabilisers alone (−13 vs −9, p = 0.003) and superiority was seen as early as week 1. In a subgroup of patients with concurrent depressive symptoms, response rates (68 vs 45%, p < 0.001) and improvements in depressive symptoms (assessed using HAM-D scores, −10.3 vs −1.57; p < 0.001) were greater with olanzapine adjunctive therapy than each study drug alone.

Tolerability

In the two placebo-controlled 3- or 4-week, double-blind trials in patients (n = 254) with bipolar I disorder, the most common adverse events (reported by at least 10% of patients treated with olanzapine 5 to 20 mg/day in either trial) were somnolence, dry mouth, dizziness, asthenia, headache, bodyweight gain, constipation, dyspepsia and anxiety; only somnolence (33 vs 17%), dry mouth (26 vs 9%), dizziness (23 vs 6%) and bodyweight gain (11 vs 1%) occurred in significantly more olanzapine than placebo recipients in at least one of the trials (p < 0.05). In comparison with valproate semisodium (500 to 2500 mg/day in divided doses), the incidence of somnolence, dry mouth and increased appetite was significantly higher with olanzapine. In these trials treatment termination due to adverse events was similar between olanzapine and placebo or valproate semisodium.

Clinically relevant changes in vital signs, laboratory tests, electrocardiogram results (including QTc interval prolongation) or haematological parameters in olanzapine recipients were not observed in either placebo-controlled study with the exception of supine systolic blood pressure in one trial. Hepatic serum transaminase levels were elevated in significantly more olanzapine than placebo recipients in both trials (18 and 17 vs 0%), although the increases were transient and clinical signs of hepatic dysfunction were not apparent.

Mean bodyweight gain with olanzapine treatment was significantly greater than that seen with placebo (1.7 and 2.1 vs −0.4 and 0.4kg) in 3- or 4-week clinical trials, and valproate semisodium in two short-term trials (2.5 and 4 vs 0.9 and 2.5kg). The incidence of EPS (assessed by standard rating scales) was comparable to that seen with placebo or valproate semisodium. There were no reports of tardive dyskinesia in 3- to 4-week placebo-controlled trials or in preliminary results of a 49-week extension phase study.

Pharmacoeconomic and Quality-of-Life Profile

Pharmacoeconomic comparisons of olanzapine and placebo generally suggest that olanzapine does not add to the overall treatment cost of patients with bipolar I disorder, and may even furnish small cost savings. Among 139 patients with bipolar I disorder treated with olanzapine 5 to 20 mg/day or placebo in a 3-week double-blind trial, total monthly outpatient ($US298 vs $US462) and inpatient costs ($US11 543 vs $US13 420) were lower with olanzapine. Moreover, during the 49-week noncomparative extension phase, total outpatient ($US89 vs $US330) and inpatient costs ($US852 vs $US1159) per month during olanzapine treatment were markedly lower than those over the previous 12 months.

Health-related quality of life tended to be comparable between patients treated with olanzapine or placebo during a 3-week double-blind trial but were superior compared with baseline in the 49-week noncomparative extension phase.

Dosage and Administration

Olanzapine is indicated in the US for the short-term treatment of acute mania associated with bipolar I disorder in patients with manic or mixed episodes with or without psychotic features. Available formulations for this indication include oral tablets and orally disintegrating tablets.

The recommended starting dosage of oral olanzapine in patients with bipolar I disorder is 10 to 15mg once daily, regardless of meals. If clinically indicated, 5mg increments or decrements at intervals ≥24 hours may be implemented within the effective therapeutic range of 5 to 20 mg/day. The safety of dosages >20 mg/day has not been assessed.

In patients predisposed to orthostatic hypotension, the risk can be minimised by dosage initiation at 5 mg/day with careful titration. Dosage modification should also be considered for patients with a combination of factors associated with slower olanzapine metabolism.

Keywords

Bipolar Disorder Haloperidol Clozapine Risperidone Olanzapine 

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© Adis International Limited 2001

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  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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